Epidermal growth factor receptor (EGFR) is a170 kilodalton membrane glycoprotein product of proto-oncogene c-erb B. EGFR gene is acellular homolog of the erb B oncogene originally identified in avian erythroblastosis viruses(1). Activation of this oncogene by gene amplification has been observed in a variety of human tumors(2-8).
EGFR has been demonstrated to be overexpressed in many types of human solid tumors(9), including lung, colon, breast, gastric, brain, bladder, head and neck, ovarian, kidney and prostate carcinomas(9). One major difference between v-erb B oncogenes and the normal EGFR gene is that the viral oncogenes are amino-truncated versions of the normal receptor: they lack most of the extracytoplasmic domain but remain the transmembrane and tyrosine kinase domains(10), which results that it is unable to bind epidermal growth factor (EGF) but still can phosphorylate other proteins(11, 12).
A variety of genetic alterations can occur in viral erb B oncogenes, e.g. substitutions and deletions of amino acids at the carboxyl terminus of the gene, wherein amino terminus truncation is critical to carcinogenesis. Amino terminus truncation is a feature of most of v-erb B oncogenes, including that arised by promoter insertion or retroviral transduction. In contrast, carboxy terminus deletions appear to be associated only with tumors arised through retroviral transduction and seem to be determined by host range and tumor type specificity. Transfection experiments conducted with amino-terminus-truncated avian c-erb B genes or human EGF receptors demonstrate that such truncation is able to create cell transformation(13).
Amplification of EGFR gene occurs in 40-50% of the malignant human gliomas(14-16). Rearrangement of the receptor gene is evident in many tumors with gene amplification. The rearrangement seems to affect the amino terminus of the gene more(17-20).
At present, eight major variants of EGFR are known: 1) EGFRvI lacks a majority of the extracellular domain of EGFR. 2) EGFRvII consists of an 83aa in-frame deletion in the extracellular domain of EGFR. 3) EGFRvIII consists of a 267aa in-frame deletion in the extracellular domain of EGFR. 4) EGFRvIV contains deletions in the cytoplasmic domain of EGFR. 5) EGFRvV contains deletions in the cytoplasmic domain of EGFR. 6) EGFR.TDM/2-7 contains a duplication of exons 2-7 in the extracellular domain of EGFR. 7) EGFR.TDM/18-26 contains a duplication of exons 18-26 in the extracellular domain of EGFR. 8) In addition, there is a second EGFRvIII mutant (EGFRvIII/Δ12-13) that possesses a novel deletion of histidine residue at the junction of exons 11 and 14(21) (FIG. 1).
EGFRvIII is the most commonly occurring variant of the epidermal growth factor (EGF) receptor in human cancers(22). During the process of gene amplification, deletion of 267 amino acids occurs in the extracellular domain, which creates a novel junction (glycine). EGFRvIII is not known to be expressed in any normal tissues(22). Yet, EGFRvIII expresses in many tumor cells, e.g., 78% breast cancer, 50˜70% gliomas, 16% NSCL cancers and 73% ovarian cancers(22). Furthermore, EGFRvIII expression was also found in hepatocellular carcinoma by the inventor's lab recently(23, 24).
However, up to now, understanding of the reasons and mechanisms for cancer invasion and metastasis is not sufficient enough. Therefore, it is urgently necessary to develop the proteins associated with tumor invasion and metastasis in the art,